4-(Alpha-hydroxy-isopropyl)-5-phenyl-oxazolidin-2-one

ABSTRACT

The present invention is related to new oxazolidin-2-one derivatives having the general formula ##STR1## The invention is further related to a process for the treatment of somnipathy and tension conditions as well as epilepsy conditions in humans by administering a compound of the above general formula to a human suffering from such conditions.

This is a division of application Ser. No. 718,610, filed Aug. 30, 1976,now U.S. Pat. No. 4,139,538, issued Feb. 13, 1979.

This invention relates to new oxazolidinones corresponding to thegeneral formula ##STR2## in which X represents hydroxy, chlorine orbromine, R₁ represents hydrogen, straight-chain or branched, saturatedor unsaturated alkyl radicals with 1 to 4 carbon atoms or benzyl, R₂represents hydrogen, straight-chain or branched, saturated orunsaturated alkyl radicals with 1 to 4 carbon atoms, the unsubstitutedphenyl radical or the phenyl radical substituted once or twice byhalogen, lower alkyl with 1 to 4 carbon atoms, lower alkoxy with 1 to 4carbon atoms and/or trifluoromethyl or the unsubstituted benzyl radicalor the benzyl radical substituted once or twice by halogen, lower alkylwith 1 to 4 carbon atoms, lower alkoxy with 1 to 4 carbon atoms and/ortrifluoromethyl, R₃ represents hydrogen, a straight-chain or branched,saturated or unsaturated alkyl radical with 1 to 4 carbon atoms, theunsubstituted phenyl radical or the phenyl radical substituted once ortwice by halogen, lower alkyl with 1 to 4 carbon atoms, lower alkoxywith 1 to 4 carbon atoms and/or trifluoromethyl or the unsubstitutedbenzyl radical or the benzyl radical substituted once or twice byhalogen, lower alkyl with 1 to 4 carbon atoms, lower alkoxy with 1 to 4carbon atoms and/or trifluoromethyl, R₄ represents hydrogen, astraight-chain or branched, saturated or unsaturated alkyl radical with1 to 4 carbon atoms or the phenyl radical, R₅ represents hydrogen, analkyl radical with 1 to 4 carbon atoms or the phenyl radical and R₆represents hydrogen, an alkyl radical with 1 to 4 carbon atoms or thephenyl radical, or R₅ and R₆ together represent an alkylene radical with4 to 6 carbon atoms in the chain.

Preferred compounds of formula I are those in which X representshydroxy, chlorine or bromine, R₁ represents hydrogen, lower alkyl with 1to 4 carbon atoms, allyl or benzyl, R₂ represents hydrogen, lower alkylwith 1 to 4 carbon atoms, allyl, unsubstituted phenyl or phenylmonosubstituted by chlorine, R₃ represents hydrogen, lower alkyl with 1to 4 carbon atoms, allyl, unsubstituted phenyl or phenyl monosubstitutedby a chlorine atom, R₄ represents hydrogen, R₅ represents hydrogen,lower alkyl with 1 to 4 carbon atoms or phenyl and R₆ representshydrogen.

Particularly favourable properties are shown by compounds of formula Iin which X represents hydroxy, chlorine or bromine, R₁ representshydrogen or methyl, R₂ represents hydrogen, methyl, phenyl,p-chlorophenyl or allyl, R₃ represents hydrogen, methyl or allyl, R₄represents hydrogen, R₅ represents hydrogen, methyl or phenyl and R₆represents hydrogen. Accordingly, these compounds are particularlypreferred.

The compounds according to the present invention may be produced bymethods known per se. In such processes, a compound corresponding to thegeneral formula ##STR3## in which Y represents a lower, straight-chainalkoxy radical with upt to 2 carbon atoms, hydrogen, straight-chain orbranched, saturated or unsaturated alkyl radical or the phenyl radicalsubstituted once or twice by halogen, lower alkyl with 1 to 4 carbonatoms, lower alkoxy with 1 to 4 carbon atoms and/or trifluoromethyl orthe unsubstituted benzyl radical or the benzyl radical substituted onceor twice by halogen, lower alkyl with 1 to 4 carbon atoms, lower alkoxywith 1 to 4 carbon atoms and/or trifluoromethyl and R₁, R₄, R₅ and R₆are as defined above, is hydrogenated with a metal hydride, for examplelithium aluminium hydride or sodium borohydride, or is reacted with anorganometallic compound corresponding to the general formula III

    R.sub.7 --Mg--Hal                                          (III)

in which R₇ is a straight-chain or branched, saturated or unsaturatedalkyl group with 1 to 4 carbon atoms, the unsubstituted phenyl group orthe phenyl group substituted once or twice by halogen, lower alkyl with1 to 4 carbon atoms, lower alkoxy with 1 to 4 carbon atoms and/ortrifluoromethyl, or the unsubstituted benzyl group or the benzyl groupsubstituted once or twice by halogen, lower alkyl with 1 to 4 carbonatoms, lower alkoxy with 1 to 4 carbon atoms and/or trifluoromethyl, andHal is a halogen atom, under the conditions of a Grignard reaction, thecompound obtained corresponding to general formula I, in which X is thehydroxyl group and R₁, R₂, R₃, R₄, R₅ and R₆ are as defined above, is,if desired, reacted with a chlorinated or brominating agent, for examplewith thionyl chloride, and X thus converted into a chlorine or,respectively, bromine atom.

The use of metal hydrides results in the formation of compounds offormula I in which R₂ represents hydrogen and R₁, R₃, R₄, R₅ and R₆ areas defined above. Application of the Grignard reaction results in theformation of compounds of formula I in which R₂ and R₃ have the samemeanings as defined above except for hydrogen.

Compounds corresponding to general formula II are known from theliterature (cf. for example G. F. Hennion and F. X. O'Shea, J.org. Chem.23, (1958) 662-664; M. E. Dyen and D. Swern, Chem.Rev. 67, (1967)197-246).

The oxazolidinones of general formula I have valuable pharmacodynamicproperties. They show outstanding anticonvulsive, tranquillizing andsleep-inducing properties and have a relaxing effect upon the centralmuscle system, and are therefore suitable for the treatment of humanssuffering from somnipathy, tensions, muscular tensions, and for thetreatment of diseases causing fits such as diseases of the petit maltype or myoclonus epilepsy and akinetic epilepsy.

Thus, when administered orally and intraperitoneally in suitable dosesto standard laboratory test animals, such as albino mice (NMRI strain,breeders Invanovas, Kissleg) and albino rats (Sprague Dawley strain,breeders Invanovas, Kissleg), the compounds according to the inventiondevelop a safe protective effect against tonic extensor cramp in themaximum electric shock test (MES) and also a safe protective effectagainst clonoc sonvulsions initiated by the subcutaneous injection of 70mg/kg of pentetrazole (minimum pentetrazole shock test=min PS). Thetoxicity of the compounds is very low. With suitable substitution, thecompounds corresponding to general formula I, especially those ofExamples 4, 5, 37, 54 and 67, are superior to a few conventionalantiepileptics, such as trimethadione and dipropyl acetate, in theanticonvulsive test models referred to.

In addition, the compounds according to the invention also differ intheir effect from conventional antiepileptics of the hydantoin type,such as diphenyl hydantoin for example, insofar as they clearly inhibitclonic cramp where as hydantoins have no effect on clonic cramp.

In addition to their anticonvulsive activity, the compounds according tothe invention have a relaxing effect upon the central muscle systemwhich is reflected in paralysis of the test animals, causing them to lieon their sides. In addition, they enhance the effect of narcotics, forexample the period of sleep following the intravenous administration of70 mg/kg of sodium hexobarbitone. With suitable substitution, compoundscorresponding to general formula I, especially those of Examples 38, 43,54 and 64, are distinctly more effective in prolonging sleep andrelaxing the muscle system than known hypnotics and tranquillizers, suchas for example chlorzoxazone and meprobamate.

The effect of some of the compounds according to the invention in animalexperiments is compared in Table 1 below with the effect of knownantiepileptics and tranquillizers.

                                      Table 1a                                    __________________________________________________________________________    Formula I                                                                      ##STR4##                                                                     Example                                                                       No.  X  R.sub.1  R.sub.2   R.sub.3  R.sub.4                                                                           R.sub.5                                                                            R.sub.6                          __________________________________________________________________________     6   OH H        H         H        CH.sub.3                                                                          CH.sub.3                                                                           C.sub.6 H.sub.5                  34   OH H        CH.sub.2 CHCH.sub.2                                                                     CH.sub.2 CHCH.sub.2                                                                    H   CH.sub.3                                                                           H                                37   OH H        CH.sub.3  CH.sub.3 H   C.sub.6 H.sub.5                                                                    H                                38   OH 3        CH.sub.3  CH.sub.3 H   C.sub.6 H.sub.5                                                                    H                                39   OH CH.sub.2 CHCH.sub.2                                                                    CH.sub.3  CH.sub.3 H   C.sub.6 H.sub.5                                                                    H                                40   OH H        C.sub.2 H.sub.5                                                                         C.sub.2 H.sub.5                                                                         H  C.sub.6 H.sub.5                                                                    H                                41   OH H        n-C.sub. 3 H.sub.7                                                                      n-C.sub. 3 H.sub.7                                                                     H   C.sub.6 H.sub.5                                                                    H                                43   OH H        CH.sub.2 CHCH.sub.2                                                                     CH.sub.2 CHCH.sub.2                                                                    H   C.sub.6 H.sub.5                                                                    H                                45   OH H        n-C.sub. 3 H.sub.7                                                                      n-C.sub. 3 H.sub.7                                                                     H   H    H                                 4   OH H        H         C.sub.6 H.sub.4 p-Cl                                                                   H   H    H                                49   OH H        C.sub.6 H.sub.4 -m-Cl                                                                   C.sub.6 H.sub.5                                                                        H   H    H                                54   OH H        C.sub.2 H.sub.5                                                                         C.sub.6 H.sub.5                                                                        H   H    H                                58   OH H        CH.sub.2CHCH.sub.2                                                                      C.sub.6 H.sub.5                                                                        H   H    H                                 5   OH H        CH.sub.3  H        H   C.sub.6 H.sub.5                                                                    H                                18   OH H        C.sub.2 H.sub.5                                                                         C.sub.6 H.sub.5                                                                        H   CH.sub.3                                                                            H                               59   OH H        CH.sub.3  C.sub.6 H.sub.4p-Cl                                                                    H   H    H                                60   OH H        C.sub.2 H.sub.5                                                                         C.sub.6 H.sub.4p-Cl                                                                    H   H    H                                64   OH CH.sub.3 C.sub.2 H.sub.5                                                                         C.sub.6 H.sub.5                                                                        H   H    H                                65   OH H        n-C.sub. 3 H.sub.7                                                                      C.sub.6 H.sub.5                                                                        H   H    H                                67   Cl H        H         H        H   C.sub.6 H.sub.5                                                                    CH.sub.3                         72   Cl H        H         H        H   C.sub.6 H.sub.5                                                                    H                                73   Br H        H         H        H   C.sub.6 H.sub.5                                                                    H                                __________________________________________________________________________

                                      Table 1b                                    __________________________________________________________________________    Formula I                                                                      ##STR5##                                                                             Anticonvulsive                                                                activity  Prolongation of                                                     MES.sup.(1)                                                                       Min PS.sup.(2)                                                                      narcosis.sup.(3)                                                                      Paralysis.sup.(4)                                                                    Acute toxicity                               Example ED.sub.50                                                                         ED.sub.50                                                                           ED.sub.200                                                                            ED.sub.50                                                                            LD.sub.50                                    No.     mg/kg p.o. (mice)                                                     __________________________________________________________________________     6      165 --*   1000    1000   >1000                                        34      150 --*   90      1000   >1000                                        37      59  130   650     1000   >1000                                        38      165 640   115     464    >1000                                        39      145 --*   130     --**     1000                                       40      75  430   165     1000   >1000                                        41      147 --*   65      --**   >1000                                        43      25  --*   15      225      1000                                       45      120 430   210     1000   >1000                                         4      125 140   160     --**   >1000                                        49      200 --*   90      --**   >1000                                        54      115 85    50      800    >1000                                        58      200 300   300     1000   >1000                                         5      75  150   510     --**   >1000                                        18      200 200   450     --**   >1000                                        59      165 --*   110     --**   >1000                                        60      175 --*   70      1000   >1000                                        64      300 --*   110     650      800                                        65      170 175   155     --**   >1000                                        67      93  55    210     1000   >1000                                        72      75  540   115     --**   >1000                                        73      65  430   420     --**   >1000                                        Na-pheno-                                                                     carbital                                                                              11  30    30      150      320                                        Trimethadione                                                                         450 240   660     --**   >1000                                        Dipropyl-                                                                     acetate 185 450   355     1000   >1000                                        Diphenyl-                                                                     hydantoin                                                                             10  ineffectual                                                                         50      no paralytic                                                                           360                                                                  effect                                              Meprobamate                                                                           115 150   150     800      1000                                       Chlorozoxazone                                                                        110 540   --*     350      650                                        __________________________________________________________________________     Key to Table 1b?                                                              .sup.(1) Effect against maximum electric shock in mice 60 minutes after       p.o. administration (stimulus data: ear electrodes, 19 mA, 4.64 msec.)        ED.sub.50 = protection against tonic extensor cramp in 50% of the animals     .sup.(2) Effect against clonic pentetrazoleinduced cramp in mice 70 mg/kg     of pentetrazole s.c., 60 minutes after p.o. administration of the             substances ED.sub.50 = protection against clonic cramp in 50% of the          animals                                                                       .sup.(3) Sodium hexobarbitone, i.v. injection of 70 mg/kg, 60 minutes         after p.o. administration of the substances ED.sub.200 = extension of the     narcosis period to 200%                                                       .sup.(4) Loss of the postural and balancing reflexes (lying down) in 50%      of the animals (ED.sub.50)                                                    .sup.(5) Acute toxicity over 7 days' post observation, maximum test dose      1000 mg/kg                                                                    *No effect up to a dose of 464 mg/kg                                          **No effect up to a dose of 1000 mg/kg                                   

Accordingly, the present invention also relates to pharmaceuticalpreparations with an anticonvulsive effect on the one hand and with asedative, sleep-including and tranquillizing effect on the other hand,containing one or more oxazolidinones of general formula I as activeprinciple.

Pharmaceutical preparations such as these may be produced by methodsknown per se to the expert in accordance with the particular form ofadministration required. They generally contain at least one activecompound according to the invention in admixture with non-toxic, inert,solid or liquid carriers and/or excipients which are suitable forsystemic use and which are normally used in preparations such as these.

Preparations for parenteral administration, for example for thetreatment of sleeplessness or cramp, may be formulated in known mannerby introducing an effective quantity of a compound of formula I into astandard inert carrier, suspension or solvent medium together with otheradditives, such as dispersants, wetting agents, buffers and otheringredients.

The preparations suitable for parenteral or oral administration maygenerally contain from 1 to 90% by weight, better still from 3 to 40% byweight, of active principle in conjunction with an inert carrier.

For treating an adult or juvenile human, each dose of the activeconstituent of a compound of general formula I administered in the formof a suitable pharmaceutical preparation such as a tablet, dragee,capsule, suspension or solution amounts to between about 10 and 500 mg.with a daily dose ranging from 30 to 1500 mg. This treatment may beeffected for 1 to several days ranging up to even one month or more.These doses apply both to the treatment of epilepsy of the Petit maltype or of myoclonus or alkinetic epilepsy and to the treatment of forinstance sleeplessness or states of superactivity.

The invention is further illustrated by the following Examples:

EXAMPLES ILLUSTRATING THE REACTION WITH METAL HYDRIDES (1)4-Hydroxymethyl oxazolidin-2-one

7.54 g (0.199 mole) of sodium borohydride are added in portions over aperiod of 1 hour to 31.7 g (0.199 mole) of 4-carboethoxyoxazolidin-2-one dissolved in 300 ml of ethanol. During the addition thetemperature rises from 15° C. to 30° C. The reaction solution is thenstirred for 1 hour at room temperature.

The reaction solution is then hydrolysed with 30 g of ammonium chloridedissolved in 400 ml of water. The pH-value then amounts to pH 5. Thissolution is concentrated to dryness and repeatedly extracted by boilingwith tetrahydrofuran. The tetrahydrofuran phases are combined andconcentrated in a rotary evaporator. The pale yellow oil is dissolved inethyl acetate. The crystals formed are filtered off under suction.

Yield: 23.4 g =97% of the theoretical, m.p.: 77°-81° C.

(2) 4-Hydroxymethyl-4-methyl-5,5-pentamethylene oxazolidin-2-one

10.92 g (0.2882 mole) of sodium borohydride are added in portions over 1hour to 59.5 g (0.262 mole) of4-carbomethoxy-4-methyl-5,5-pentamethylene oxazolidin-2-one dissolved in600 ml of ethanol. The reaction solution is then stirred for 12 hours atroom temperature. It is then poured carefully into a saturated NH₄Cl-solution until the pH-value amounts to pH 5. This solution isrepeatedly extracted with chloroform. The combined chloroform phases aredried over Na₂ SO₄ and concentrated in a rotary evaporator. The paleyellow oil is taken up in ether. Crystals precipitate after a shorttime.

Yield: 43.0 g=82.5% of the theoretical, m.p.: 113°-115° C.

(3) 4-(α-Hydroxybenzyl)-oxazolidin-2-one

3 g (15.8 mMole) of 4-benzoyl oxazolidin-2-one are dissolved in 100 mlof ethanol, followed by the addition in portions at room temperature of900 mg (23.8 mMole) of sodium borohydride. The mixture is then stirredfor 2.5 hours at room temperature. The reaction solution is thenhydrolysed with a saturated ammonium chloride solution. The aqueousphase is repeatedly extracted with CHCl₃, the organic phases arecombined, dried over Na₂ SO₄ and concentrated in a rotary evaporator.The oil is taken up in methanol. The crystals are filtered undersuction.

Yield: 2.2 g=75% of the theoretical, m.p.: 130°-140° C.

(4) 4-(α-Hydroxy-p-chlorobenzyl)-oxazolidin-2-one

1 g (4.4 mMole) of 4-(p-chlorobenzoyl)-oxazolidin-2-one is dissolved in50 ml of ethanol, followed by the addition in portions at roomtemperature of 300 mg (8.0 mMole) of sodium borohydride. After 1 hour, asaturated NH₄ Cl-solution is added to the reaction solution which isthen repeatedly extracted with chloroform. The combined organic phasesare dried over Na₂ SO₄ and concentrated. The yellow oil is taken up inether/hexane. The crystals formed are filtered off under suction.

Yield: 0.5 g=50% of the theoretical, m.p.: 126°-128° C.

(5) 4-[1-(1-Hydroxyethyl)]-5-phenyl oxazolidin-2-one

7.2 g (0.190 mole) of sodium borohydride are added in portions over aperiod of 1 hour to 3.8 g (0.018 mole) of 4-acetyl-5-phenyloxazolidin-2-one dissolved in 50 ml of ethanol. The reaction solution isthen stirred for 1 hour at room temperature, followed by the addition ofa saturated ammonium chloride solution and repeated extraction withchloroform. The combined chloroform phases are dried and concentrated.The yellow oil is taken up in a little methanol. The crystals formed arefiltered under suction.

Yield: 3 g=78.5% of the theoretical, m.p.: 133°-134° C.

The following derivatives are produced in accordance with theseExamples:

    __________________________________________________________________________     ##STR6##                                                                     Example                                                                       No.  R.sub.1                                                                         R.sub.3  R.sub.4                                                                          R.sub.5                                                                          R.sub.6                                                                          m.p. °C.                                      __________________________________________________________________________     6   H H        CH.sub.3                                                                         CH.sub.3                                                                         C.sub.6 H.sub.5                                                                  168-170                                                                       (ethanol)                                             7   H H        H  C.sub.6 H.sub.5                                                                  C.sub.6 H.sub.5                                                                  163-165                                                                       (ethyl acetate)                                       8   H H        H  H  C.sub.6 H.sub.5                                                                  103-105                                                                       (methanol/isopropyl ether)                            9   H H        H  CH.sub.3                                                                         C.sub.6 H.sub.5                                                                  100-101                                                                       (ethyl acetate)                                      10   H                                                                                ##STR7##                                                                              H  H  H  105-107 (ether/hexane)                               11   H                                                                                ##STR8##                                                                              H  H  H  117-119 (ether/petroleum ether)                      12   H                                                                                ##STR9##                                                                              H  H  H  124-126 (isopropyl ether/hexane)                     13   H                                                                                ##STR10##                                                                             H  H  H  131-133 (methanol/isopropyl ether)                   __________________________________________________________________________

EXAMPLES ILLUSTRATING THE APPLICATION OF GRIGNARD REACTIONS (14)4-[1-(1-n-Butyl-1-hydroxy)-n-pentyl]-5-phenyl oxazolidin-2-one

11.06 g (0.05 mole) of 4-carbomethoxy-5-phenyl oxazolidin-2-onedissolved in 100 ml of absolute tetrahydrofuran are slowly addeddropwise to a Grignard solution prepared from 20.5 ml (0.2 mole) ofn-butyl bromide in 50 ml of absolute ether and 4.86 g (0.2 gramequivalent) of Mg in 20 ml of absolute ether. The reaction temperatureshould not rise above +16° C. during the dropwise addition. When after 1hour the tetrahydrofuran solution has been added, the reaction solutionis stirred for another 1.5 hours at 30° C., subsequently hydrolysed witha saturated NH₄ Cl-solution and repeatedly extracted with ether. Theorganic phases are combined and dried over Na₂ SO₄. The solvent isdistilled off. The residue becomes crystalline.

Yield: 7.1 g=46% of the theoretical, m.p.: 130°-132° C.

(15) 3-N-Methyl-4-[1-(1-hydroxy-1-methyl)-ethyl]-5,5-diphenyloxazolidin-2-one

7.82 g (0.024 mole) of 3-N-methyl-4-carboethoxy-5,5-diphenyloxazolidin-2-one dissolved in 200 ml of absolute tetrahydrofuran areslowly added dropwise under nitrogen to a Grignard solution preparedfrom 2.9 g (0.12 mole) of magnesium and 17 g (0.12 mole) of methyliodide in 100 ml of absolute ether. The reaction temperature is in therange from 25° to 30° C. The reaction solution is then heated underreflux for 2 hours to boiling point. It is then hydrolysed with asaturated NH₄ Cl-solution. The precipitated product is filtered offunder suction.

Crude product: 7.64 g, m.p.: 195°-210° C.

This substance is recrystallised twice from ethanol.

Yield: 2.5 g=33.5% of the theoretical, m.p.: 215°-217° C.

(16) 4-[α-(Hydroxy-p-tolyl)-benzyl]-oxazolidin-2-one

5.0 g (26.2 mMole) of 4-benzoyl oxazolidin-2-one dissolved in 100 ml ofabsolute tetrahydrofuran are slowly added dropwise at 10° to 15° C. to aGrignard solution prepared from 9 ml (75.8 mMole) of p-chlorotoluene and1.84 g (0.076 gram equivalents) of magnesium in 150 ml of absolutetetrahydrofuran. The reaction solution is then stirred for 1 hour atroom temperature, hydrolysed with ice-ammonium chloride and repeatedlyextracted with ether. The combined organic phases are dried over Na₂ SO₄and concentrated. The pale yellow oil is taken up inisopropanol/isopropyl ether. The crystals formed are filtered off undersuction.

Yield: 2.5 g=35.3% of the theoretical, m.p.: 216°-218° C.

(17) 4-[α-(Hydroxy cyclohexyl)-benzyl]-oxazolidin-2-one

5.0 g (0.0262 mole) of 4-benzoyl oxazolidin-2-one dissolved in 100 ml ofabsolute tetrahydrofuran are added dropwise while cooling with ice to aGrignard solution prepared from 12.8 ml (0.127 mole) of bromocyclohexaneand 2.98 g (0.128 gram equivalent) of magnesium in 150 ml of absolutetetrahydrofuran. This solution is stirred for 2 hours at 60° C.,subsequently hydrolysed with approximately 500 ml of a saturatedammonium chloride solution and repeatedly extracted with chloroform. Theorganic phases are combined, dried over Na₂ SO₄ and concentrated in arotary evaporator. The oil is taken up in ether. The crystals formed arefiltered off under suction.

Yield: 2.5 g=35% of the theoretical, m.p.: 190°-192° C.

(18) 4-[-1-(1-Hydroxy-1-phenyl)-propyl]-5-methyl oxazolidin-2-one

10.26 g (0.05 mole) of 4-benzoyl-5-methyl oxazolidin-2-one dissolved in250 ml of absolute tetrahydrofuran are added dropwise under nitrogenwhile cooling with ice to a Grignard solution prepared from 7.30 g (0.3gram equivalent) of magnesium and 35.96 g (0.33 mole) of ethyl bromidein 120 ml of absolute ether. The internal temperature rises from +2° C.to +12° C. The reaction solution is then heated under reflux for 1 hourto boiling point, hydrolysed with a saturated ammonium chloride solutionand repeatedly extracted with ether. The organic phases are combined,dried and concentrated. 12.85 g of a solid residue are obtained, beingrecrystallised from 60 ml of methanol.

Yield: 8.3 g=70% of the theoretical, m.p.: 192°-194° C.

The derivatives listed in Table 2 below were similarly prepared.

                                      Table 2                                     __________________________________________________________________________     ##STR11##                                                                    Example                                                                       No.  R.sub.1   R.sub.2     R.sub.3    R.sub.4                                                                         R.sub.5                                                                            R.sub.6                                                                            M.p. °C.             __________________________________________________________________________    19   H         C.sub.6 H.sub.5                                                                           C.sub.6 H.sub.5                                                                          H H    H    205-207                                                                       (methanol/ether)            20   H         m-ClC.sub.6 H.sub.4                                                                       m-ClC.sub.6 H.sub.4                                                                      H H    H    173-174                                                                       (methanol)                  21   H         o-CH.sub.3 OC.sub.6 H.sub.4                                                               o-CH.sub.3 OC.sub.6 H.sub.4                                                              H H    H    172-173                                                                       (benzene)                   22   H         m-CH.sub.3 OC.sub.6 H.sub.4                                                               m-CH.sub.3 OC.sub.6 H.sub.4                                                              H H    H    134-135                                                                       (benzene)                   23   H         p-CH.sub.3 OC.sub.6 H.sub.4                                                               p-CH.sub.3 OC.sub.6 H.sub.4                                                              H H    H    118-120                                                                       (benzene)                   24   H         o-CH.sub.3C.sub.6 H.sub.4                                                                 o-CH.sub.3C.sub.6 H.sub.4                                                                H H    H    208-210                                                                       (methanol/ether)            25   H         m-CF.sub.3C.sub.6 H.sub.4                                                                 m-CF.sub.3C.sub.6 H.sub.4                                                                H H    H    178-180                                                                       (ether/isopropanol)         26   H         m-FC.sub.6 H.sub.4                                                                        m-FC.sub.6 H.sub.4                                                                       H H    H    184-186                                                                       (ether)                     27   H         CH.sub.2C.sub.6 H.sub.5                                                                   CH.sub.2C.sub.6 H.sub.5                                                                  H H    H    173-174                                                                       (methanol/isopropyl                                                           ether)                      28   H                                                                                        ##STR12##                                                                                 ##STR13## H H    H    163-165 (methanol)          29   H         CH.sub.2CHCH.sub.2                                                                        CH.sub.2CHCH.sub.2                                                                       H H    H    96-97                                                                         (methanol/isopropyl                                                           ether)                      30   H         C.sub.6 H.sub.5                                                                           C.sub.6 H.sub.5                                                                          H H    CH.sub.3                                                                           215-217                                                                       (methanol)                  31   H         m-ClC.sub.6 H.sub.4                                                                       m-ClC.sub.6 H.sub.4                                                                      H H    CH.sub.3                                                                           220-221                                                                       (isopropyl ether)           32   H         CH.sub.2C.sub.6 H.sub.5                                                                   CH.sub.2C.sub.6 H.sub.5                                                                  H H    CH.sub.3                                                                           93-94                                                                         (isopropyl ether)           33   H                                                                                        ##STR14##                                                                                 ##STR15## H H    CH.sub.3                                                                           100-101 (isopropyl                                                            ether)                      34   H         CH.sub.2CHCH.sub.2                                                                        CH.sub.2CHCH.sub.2                                                                       H H    CH.sub.3                                                                           90-91                                                                         (isopropyl ether)           35   H         C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5                                                                          H H    CH.sub.3                                                                           69-70                                                                         (isopropyl ether)           36   H         n-C.sub.4 H.sub.9                                                                         n-C.sub.4 H.sub.9                                                                        H H    CH.sub.3                                                                           118- 119                                                                      (isopropyl ether)           37   H         CH.sub.3    CH.sub.3   H H    C.sub.6 H.sub.5                                                                    203-204                                                                       (methanol/ether)            38   CH.sub.3  CH.sub.3    CH.sub.3   H H    C.sub.6 H.sub.5                                                                    100-101                                                                       (acetic acid-n-butyl                                                          ester)                      39   CH.sub.2CHCH.sub.2                                                                      CH.sub.3    CH.sub.3   H H    C.sub.6 H.sub.5                                                                    92-93                                                                         (acetic acid-n-butyl                                                          ester)                      40   H         C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5                                                                          H H    C.sub.6 H.sub.5                                                                    160-161                                                                       (methanol)                  41   H         n-C.sub.3 H.sub.7                                                                         n-C.sub.3 H.sub.7                                                                        H H    C.sub.6 H.sub.5                                                                    136-138                                                                       (ether)                     42   H         C.sub.6 H.sub.5                                                                           C.sub.6 H.sub.5                                                                          H H    C.sub.6 H.sub.5                                                                    238-239                                                                       (methanol)                  43   H         CH.sub.2CHCH.sub.2                                                                        CH.sub.2CHCH.sub.2                                                                       H H    C.sub. 6 H.sub.5                                                                   115-117                                                                       (isopropanol)               44   H         C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5                                                                          H H    H    106-107                                                                       (methanol/isopropyl                                                           ether)                      45   H         n-C.sub.3 H.sub.7                                                                         n-C.sub.3 H.sub.7                                                                        H H    H    120-121                                                                       (ether)                     46   CH.sub.2C.sub.6 H.sub.5                                                                 CH.sub.3    CH.sub.3   H H    C.sub.6 H.sub.5                                                                    90-91                                                                         (ethyl acetate)             47   H         CH.sub.3    CH.sub.3   H C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    239-240                                                                       (ethanol)                   48   H         CH.sub.2 CHCH.sub.2                                                                       CH.sub.2CHCH.sub.2                                                                       H C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    138-139                                                                       (ether)                     49   H         m-ClC.sub.6 H.sub.4                                                                       C.sub.6 H.sub.5                                                                          H H    H    155-157                                                                       (ether)                     50   H         p-ClC.sub.6 H.sub.4                                                                       C.sub.6 H.sub.5                                                                          H H    H    116-118                                                                       (isopropylether/                                                              isopropanol)                51   H         m-CF.sub.3C.sub.6 H.sub.4                                                                 C.sub.6 H.sub.5                                                                          H H    H    151-153                                                                       (hexane/ether)              52   H         o-ClC.sub.6 H.sub.4                                                                       C.sub.6 H.sub.5                                                                          H H    H    195-197                                                                       (benzene)                   53   H         m-FC.sub.6 H.sub.4                                                                        C.sub.6 H.sub.5                                                                          H H    H    189-191                                                                       (benzene)                   54   H         C.sub.2 H.sub.5                                                                           C.sub.6 H.sub.5                                                                          H H    H    192-195                                                                       (ether/hexane)              55   H         CH.sub.2C.sub.6 H.sub.5                                                                   p-CH.sub.3C.sub.6 H.sub.4                                                                H H    H    168-171                                                                       (ether)                     56   H         CH.sub.2C.sub.6 H.sub.5                                                                   C.sub.6 H.sub.5                                                                          H H    H    199-203                                                                       (ether)                     57   H         o-CH.sub.3OC.sub.6 H.sub.4                                                                C.sub.6 H.sub.5                                                                          H H    H    174-176                                                                       (ether)                     58   H         CH.sub.2CHCH.sub.2                                                                        C.sub.6 H.sub.5                                                                          H H    H    112-113                                                                       (methanol)                  59   H         CH.sub.3    C H -p-Cl  H H    H    115-118                                                                       (ether)                     60   H         C.sub.2 H.sub.5                                                                           C.sub.6 H.sub.4 -p-Cl                                                                    H H    H    176-179                                                                       (methanol/ether)            61   H         CH.sub.3    C.sub.6 H.sub.5                                                                          H H    H    198-200                                                                       (methanol)                  62   H         C.sub.2 H.sub.5                                                                            ##STR16## H H    H    184-186 (methanol/ether)                                                      1                           63   H         C.sub.2 H.sub.5                                                                            ##STR17## H H    H    108-110 (methanol)          64   CH.sub.3  C.sub.2 H.sub.5                                                                           C.sub.6 H.sub.5                                                                          H H    H    172-173                                                                       (methanol/isopropyl                                                           ether)                      65   H         n-C.sub.3 H.sub.7                                                                         C.sub.6 H.sub.5                                                                          H H    H    172-173                                                                       (methanol/isopropyl                                                           ether)                      66   H         CH.sub.3    n-C.sub.4 H.sub.9                                                                        H C.sub.6 H.sub.5                                                                    H    160-161                                                                       (benzene/isopropyl                                                            ether)                      __________________________________________________________________________

EXAMPLES ILLUSTRATING THE OPTIONAL REACTION WITH A HALOGENATING AGENT(67) 4-Chloromethyl-5-methyl-5-phenyl oxazolidin-2-one

1.5 ml (10 mMole) of thionyl chloride are slowly added dropwise at 0° to+5° C. to 1.04 g (5 mMole) of 4-hydroxymethyl-5-methyl-5-phenyloxazolidin-2-one dissolved in 15 ml of pyridine. After 1 hour at 50° C.,the reaction solution is stirred overnight at room temperature, pouredonto ice and repeatedly extracted with chloroform. The combinedchloroform phases dried over Na₂ SO₄ are concentrated. The crystalsformed are recrystallised from methanol.

Yield: 0.56 g=50% of the theoretical, m.p.: 150°-152° C.

The derivatives listed in Table 3 below were similarly prepared.

                                      Table 3                                     __________________________________________________________________________     ##STR18##                                                                    Example                                                                       No.  X R.sub.1                                                                         R.sub.2                                                                            R.sub.3                                                                            R.sub.4                                                                           R.sub.5                                                                            R.sub.6                                                                            m.p. °C.                              __________________________________________________________________________    68   Cl                                                                              H C.sub.2 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    H   H    H    170-172                                                                       (benzene)                                    69   Cl                                                                              H H    H    H   H    H    oil, B.p. 140° C./0.02 Torr           70   Cl                                                                              H H    H    CH.sub.3                                                                          (CH.sub.2).sub.5                                                                        175-180                                                                       (methanol)                                   71   Cl                                                                              H H    H    H   C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    200-202                                                                       (ethanol)                                    72   Cl                                                                              H H    H    H   C.sub.6 H.sub.5                                                                    H    126-128                                                                       (methanol)                                   73   Br                                                                              H H    H    H   C.sub.6 H.sub.5                                                                    H    117-118                                                                       (methanol)                                   74   Br                                                                              H H    H    H   H    H    65-68                                                                         (ethyl acetate/petroleum                     __________________________________________________________________________                                     ether)                                   

PRACTICAL EXAMPLES EXAMPLE 75

A tablet consists of 100 mg of the compound according to Example 33, 10mg of tragacanth, 147.5 mg of lactose, 25 mg of corn starch, 15 mg oftalcum and 2.5 mg of magnesium stearate. The active principle isgranulated with the lactose mixture in the usual way, magnesium stearateis added and the mixture is pressed into tablets in the usual way.

EXAMPLE 76

A dragee consists of 20 mg of the compound of Example 27, 110 mg oflactose, 25 mg of Avicel and 5 mg of talcum. The constituents are mixedand the mixture pressed in the usual way into tablets 8 mm in diameterand weighing 160 mg. The tablets are then coated with sugar syrup to aweight of 250 mg.

EXAMPLE 77

A capsule consists of 300 mg of the compound of Example 67 and 10 mg oftalcum. The active principle is mixed with the talcum mixture and hardgelatin capsules filled with the resulting mixture.

EXAMPLE 78

A suspension consists of 1.0 g of the compound of Example 27, 2.0 g ofbentonite, 1.5 g of sodium carboxymethyl cellulose, 30 g of sugar, 0.3 gof potassium sorbate and 0.01 g of peppermint aroma. The finely groundactive principle is mixed with the above-mentioned excipients and asuspension 100.0 g in weight is prepared in the usual way by addingwater. The individual dose amounts to between 1 and 3 teaspoons full.

EXAMPLE 79

A solution suitable for intravenous administration contains 5% by weightof the compound of Example 33, the quantity of sodium chloride requiredfor forming an isotonic solution, 10 to 20% by weight of ethanol, 15 to25% by weight of propylene glycol and 15 to 75% by weight of watersuitable for injection.

EXAMPLE 80

A tablet produced in accordance with Example 75 consisting of 50 mg. ofthe active compound according to Example 43 and the equivalent amount ofthe other ingredients was administered to a human suffering from motorrestlessness. Within a period of several minutes the patient reported amuscle relaxing, tiring and ataraktic sedation. Studies of anelectroencephalogram showed the characteristic signs of a sedation witha decrease of effectiveness in the alpha and beta band and a change ofthe range of main activity to the lower frequency range. Indications ofa shallow sleep phase clearly increased in the electroencephalogramregistered 5 hours after administration of the drug.

We claim:
 1. 4-[1'(1'-Hydroxy-1'-methyl)-ethyl]-5-phenyloxazolidin-2-one corresponding to the formula ##STR19##